Roles of Iron-Dependent PHD and JARID in Early-Life Iron Deficiency-Induced Adult Neural Gene Dysregulation

摘要 早产期缺铁(ID)影响全球约20%-30%的孕妇及其后代， 导致成年后长期的认知和社会情绪行为障碍，尽管铁剂治疗 在婴儿期被诊断为ID后。这些持续的异常现象在#年给社会造成了巨大的代价。 关于失去教育、工作潜力和精神健康的条款。持续性肺炎的潜在病理生物学 行为异常被完全归因于神经发育和功能的异常(例如， 新陈代谢、树突发生和突触发生)在生命早期的关键时期 进入成年期(功能遵循假设)。然而，知识方面的主要差距仍然存在，其中之一 与铁依赖的细胞机制有关，通过这种机制，早期生命ID诱导基因调控失调 对成年后的神经元功能至关重要。这些知识对于推动治疗领域的发展至关重要。 预防早期营养不良对大脑发育的长期负面影响的策略。 目前的提案调查了由含铁双加氧酶驱动的细胞通路如何改变 主要突触分化和可塑性基因的神经元长期表达，包括脑源性基因 神经营养因子(BDNF)。我们利用铁的必要性进行催化活性的两个众所周知 含组蛋白去甲基酶的双加氧酶、脯氨酸羟基酶和JmjC干旱结构域家族 (JARIDs)，分析早期ID对神经组织中这些蛋白质的功能影响。我们的小说 概念化认为，这两条通路是通过对HIF1α的PHD调节连接在一起的，而HIF1DNA又是靶标 贾里德。根据我们最近发表的发现和新的初步数据，我们将展示早期生命ID会发生变化 PHD和JARID的功能，导致稳定的表观遗传修饰和后续基因 成年后的调节失调。我们将使用我们独特的慢性缺铁初级患者来验证这一新的假设 海马神经元培养模型及显性阴性TfR1转基因小鼠模型的建立 它被设计成在发育中的神经元中以时间依赖的方式特异性地诱导ID，而不是 全身性贫血或全球脑ID。我们将使用以下内容进一步证明这一概念的翻译价值 饮食中的缺铁性贫血大鼠模型与人类的情况非常相似。 拟议的工作将对实地产生重大影响，因为它解决了知识中的两个重要差距： (1)PHD和JARID是否是直接导致染色质变化的关键含铁因素 结构，导致对学习和记忆至关重要的基因持续失调；以及(2) 及时的铁修复可以减弱这些改变。缩小这些差距在设计战略时至关重要， 包括在怀孕期间保持铁的充足，以及设计潜在的治疗方法来恢复 表观遗传景观(例如，胆碱)，以减轻数百万早产儿的终生负担。

ABSTRACT Early-life iron deficiency (ID) affects ~20-30% of all pregnant women and their offspring worldwide and causes long-term impairments in cognition and socio-emotional behaviors in adulthood despite iron therapy after the diagnosis of ID in infancy. These persistent abnormalities constitute a significant cost to society in terms of loss of education, job potential, and mental health. The underlying pathobiology for the persistent behavioral abnormalities has been ascribed solely to abnormal neural development and function (e.g., metabolism, dendritogenesis, and synaptogenesis) during critical periods in early life that are carried forward into adulthood (function follows form hypothesis). However, major gaps in knowledge remain, one of which pertains to the iron-dependent cellular mechanisms, by which early-life ID induces the dysregulation of genes critical for neuronal function in adulthood. Such knowledge is critical to advance the field in terms of therapeutic strategies to prevent the long-term negative effects of early-life ID on the developing brain. The present proposal investigates how cellular pathways driven by iron-containing dioxygenases alter long-term neuronal expression of major synaptic differentiation and plasticity genes, including brain-derived neurotrophic factor (BDNF). We leverage the necessity of iron for the catalytic activity of two well-known families of dioxygenases, prolyl hydroxylases (PHDs) and JmjC ARID-domain containing histone demethylases (JARIDs), to analyze the functional effect of early-life ID on these proteins in neural tissues. Our novel conceptualization is that the two pathways are linked through PHD regulation of HIF1α, which in turns targets JARIDs. Based on our recent published findings and new preliminary data, we will show that early-life ID alters the function of both PHD and JARID, leading to stable epigenetic modifications and consequent gene dysregulation in adulthood. We will test this novel hypothesis using our unique chronic iron-deficient primary cultured hippocampal-pyramidal neuron model and our dominant-negative (DN) TfR1 transgenic mouse model that was engineered to induce ID specifically in the developing neurons in a time-dependent manner without systemic anemia or global brain ID. We will further demonstrate the translational value of this concept using the dietary ID anemia rat model that closely resembles the human condition. The proposed work will have a major impact on the field by addressing two important gaps in knowledge: (1) whether PHDs and JARIDs are key iron-containing factors directly responsible for the changes in chromatin structures, resulting in the persistent dysregulation of genes critical for learning and memory; and (2) whether timely iron restoration can attenuate these modifications. Closing these gaps is crucial in designing strategies, including maintenance of iron sufficiency during pregnancy and devising potential therapies that restore the epigenetic landscape (e.g., choline), to lessen the life-long burden of millions of children with early-life ID.